Reduced functional connectivity in a right-hemisphere network for volitional ocular motor control in schizophrenia.

1Institute of Neuroscience, School of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan.

Abstract

Patients with schizophrenia consistently show deficient performance on tasks requiring volitional saccades. We previously reported reduced fractional anisotropy in the white matter underlying right dorsal anterior cingulate cortex in schizophrenia, which, along with lower fractional anisotropy in the right frontal eye field and posterior parietal cortex, predicted longer latencies of volitional saccades. This suggests that reduced microstructural integrity of dorsal anterior cingulate cortex white matter disrupts connectivity in the right hemisphere-dominant network for spatial attention and volitional ocular motor control. To test this hypothesis, we examined functional connectivity of the cingulate eye field component of this network, which is located in dorsal anterior cingulate cortex, during a task comprising volitional prosaccades and antisaccades. In patients with schizophrenia, we expected to find reduced functional connectivity, specifically in the right hemisphere, which predicted prolonged saccadic latency. Twenty-seven medicated schizophrenia outpatients and 21 demographically matched healthy controls performed volitional saccades during functional magnetic resonance imaging. Based on task-related activation, seed regions in the right and left cingulate eye field were defined. In both groups, the right and left cingulate eye field showed positive correlations with the ocular motor network and negative correlations with the default network. Patients showed reduced positive functional connectivity of the cingulate eye field, specifically in the right hemisphere. Negative functional connectivity of the right cingulate eye field predicted faster saccades, but these relations differed by group, and were only present in controls. This pattern of relations suggests that the coordination of activity between ocular motor and default networks is important for efficient task performance and is disrupted in schizophrenia. Along with prior observations of reduced white matter microstructural integrity (fractional anisotropy) in schizophrenia, the present finding of reduced functional connectivity suggests that functional and structural abnormalities of the right cingulate eye field disrupt connectivity in the network for spatial attention and volitional ocular motor control. These abnormalities may contribute to deficits in overcoming prepotency in the service of directing eye gaze and attention to the parts of the environment that are the most behaviourally relevant.

Saccadic paradigm with idealized eye position traces. Saccadic trials lasted 4000 ms and began with an instructional cue at the centre of the screen. For half of the participants, orange concentric rings were the cue for a prosaccade trial (A) and a blue cross was the cue for an antisaccade trial (B). These cues were reversed for the rest of the participants. The cue was flanked horizontally by two small green squares of 0.2° width that marked the potential locations of stimulus appearance, 10° left and right of centre. These squares remained on the screen for the duration of each run. (C) At 300 ms, the instructional cue was replaced by a green fixation ring at the centre of the screen, of 0.4° diameter and luminance of 20 cd/m2. After 1700 ms, the ring shifted to one of the two target locations, right or left, with equal probability. This was the stimulus to which the participant responded by either making a saccade to it (prosaccade) or to the square on the opposite side (anti saccade). The green ring remained in the peripheral location for 1000 ms and then returned to the centre, where participants were also to return their gaze for 1000 ms before the start of the next trial. Fixation intervals were simply a continuation of the fixation display that constituted the final second of the previous saccadic trial.

Regions showing significant (false-discovery rate corrected P < 0.001) positive and negative functional connectivity with left and right CEF in the combined group data displayed on the lateral and medial inflated cortical surfaces.

Statistical maps of regionally specific group differences in the positive functional connectivity of the right CEF displayed on the averaged structural MRI image of study participants registered to the MNI152 atlas (Collins et al., ). Schizophrenia participants showed reduced functional connectivity in the (a) left thalamus, (b) right pre-supplementary motor area (SMA), and (c) right anterior insula.

Scatter plots of the age-corrected regressions of negative functional connectivity (FC) of the right cingulate eye field on (A) antisaccade latency and (B) prosaccade latency by group. Regression lines are given for controls (HC) and patients (SZ) separately. Only for controls is negative functional connectivity of the right CEF related to saccadic latency.